tbuckley/cabot-search huggingface dataset:
Detection of DNA adduct γ-OHPdG in circulating tumor cells (CTCs) and its use as a prognostic biomarker in patients with hepatocellular carcinoma (HCC).
Authors: Aiwu Ruth He, Fung-Lung Chung, Monika Aggarwal, Zizhao Zhu, Sophie Gould, Kevin Zhang, Mark Kuo, Peter Johnson, Samira Beheshtian, Laura Kuhlman, Zijun Zhao, Hongbin Fang, Bhaskar Kallakury, Karen Creswell, Alexander Kroemer
Journal: Journal of Clinical Oncology (2023)

594 Background: A blood-based biomarker to predict the risk of hepatocellular carcinoma (HCC), and its recurrence is needed. Previously, we showed that γ-OHPdG, a mutagenic DNA adduct formed by lipid peroxidation, in liver biopsies from HCC patients, as detected by IHC, is inversely associated with overall survival (p&lt;0.0001) and recurrence-free survival (p&lt;0.007) after surgical resection. This finding suggests that γ-OHPdG may serve as a prognostic biomarker of HCC and its recurrence. A non-invasive method to detect γ-OHPdG is needed. Liquid biopsy is preferred over tissue biopsy because it is non-invasive, allows repeated sampling, lower risk to patient, and lower medical care cost. We developed a non-invasive method for detecting and quantifying γ-OHPdG using CTCs from HCC patient. Methods: The method involved following steps. First, CTCs from blood samples were isolated using a RosetteSep CD45 Depletion Cocktail and Ficoll Paque-based method. Isolated cells were identified as liver CTCs using asialoglycoprotein receptor 1 (ASGPR1), a cell surface protein expressed solely on the surface of hepatic cells, and γ-OHPdG by immunocytochemistry. The percentage of ASGPR1 and γ-OHPdG-positive stained CTCs and γ-OHPdG staining intensity was quantified using Metamorph software. The staining intensities in livers CTCs will be compared with that found in liver biopsies by IHC. Results: To determine the sensitivity and specificity of testing -γ-OHPdG level in circulating tumor cells using an-anti γ-OHPdG antibody, we showed that the proportion of γ-OHPdG-positively stained cells and staining intensity increased in HepG2 liver cancer cells upon acrolein treatment at increasing concentration. Furthermore, when the HepG2 was used to spike blood of healthy volunteers’, the recovery rate of γ-OHPdG positivity was &gt; 50-60%. CTCs from 32 HCC patients, detected at a positivity rate of ~97%, were tested for γ-OHPdG levels using the method developed in this project. The clinical factors including demographics, risk factors, alpha-fetoprotein (AFP), HCC size, multifocality, vascular invasion, extrahepatic metastasis have been correlated with the levels of γ-OHPdG in CTCs. Conclusions: The CTC method developed for detecting and quantifying γ-OHPdG warrant validations as a prognostic biomarker for predicting HCC risk and recurrence in clinical trials.
MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress.
Authors: Tanios S. Bekaii-Saab, Eric Van Cutsem, Josep Tabernero, Salvatore Siena, Takayuki Yoshino, Yoshiaki Nakamura, Kanwal Pratap Singh Raghav, Andrea Cercek, Volker Heinemann, David E. Adelberg, James Edward Ward, Shan Yang, Thierry Andre, John H Strickler
Journal: Journal of Clinical Oncology (2023)

TPS261 Background: Current standard of care (SOC) for treatment (tx) of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, w/ or w/o a VEGF- or EGFR-inhibitor. HER2 is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%-5% of patients (pts) w/ mCRC; the rate of HER2 amplification can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC), a highly selective, HER2-directed tyrosine kinase inhibitor, is approved in multiple regions for HER2+ metastatic breast cancer and is being investigated in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in pts w/ tx refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity (confirmed ORR of 38.1% and median DOR of 12.4 months) and demonstrated TUC + Tras was well tolerated with a low discontinuation rate (5.8%) and no deaths due to AEs. MOUNTAINEER-03 will further investigate TUC in combo w/ mFOLFOX and Tras in pts w/ RAS wild-type, HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open label, randomized, phase 3 study for 1L tx of HER2+ and RAS wild-type mCRC. Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab). HER2 status is determined centrally w/ tissue based HER2 immunohistochemistry and in situ hybridization assays. Eligible pts must not have received prior tx in the metastatic setting but may have received adjuvant tx if completed &gt; 6 months prior to enrollment. Pts must be ≥18 years of age w/ an ECOG performance status of ≤1 and RAS wild-type mCRC. Pts w/ treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). Primary endpoint is progression-free survival per RECIST v1.1, assessed by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate per RECIST v1.1 assessed by BICR. Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651 .
Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: A large, real-life, worldwide population.
Authors: Margherita Rimini, Andrea Casadei-Gardini, Mara Persano, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Jaekyung Cheon, Fabian Finkelmeier, Lorenza Rimassa, Josè Presa, Gianluca Masi, Changhoon Yoo, Sara Lonardi, Francesco Tovoli, Mario Scartozzi, Valentina Burgio, Stefano Cascinu, Alessandro Cucchetti
Journal: Journal of Clinical Oncology (2023)

579 Background: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomized controlled trial. We conducted a retrospective multi-center study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. Methods: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint. Results: The analysis included 1,341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p=0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p=0.024). Conversely, OS was prolonged by lenvatinib in patients with NASH/NAFLD (HR: 1.88; p=0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. Conclusions: Our study did not identify any meaningful difference in overall survival between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with NASH/NAFLD might benefit more from lenvatinib therapy and patients with viral etiology more from atezolizumab plus bevacizumab.
A multicenter study to investigate the role of sarcopenia as a prognostic factor in patients with hepatocellular carcinoma treated by trans-arterial radioembolization.
Authors: Heechul Nam, Hyun Yang, Yeon Seok Seo, Do Young Kim, Yoon Jun Kim, Si Hyun Bae
Journal: Journal of Clinical Oncology (2023)

532 Background: Trans-arterial radioembolization (TARE) is a form of radiation therapy performed by selective intra-arterial injection of microspheres loaded with Yttrium-90 in hepatocellular carcinoma (HCC). The aim of this study is to identify prognostic factors for overall survival (OS) and progression free survival (PFS) in patients with HCC undergoing TARE. Methods: This is a multi-center retrospective study on consecutive HCC patients undergoing TARE from Jul 2009 to May 2019. Using pre-treatment plain computed tomography imaging, the total cross-sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing muscle area to patient height. Results: A total of 347 patients were included in the study (mean age 66 years, 284 male patients). 107 patients (30.8%) had portal vein tumor thrombus (PVTT). 126 patients (36.3%) were classified as sarcopenia. Median 5-year OS was 31.3 months (95% CI 24.7–37.9) and median 12-month PFS was 9.7 months (95% CI 8.0–11.4). Sarcopenia (HR, 1.44; 95% CI, 1.01-2.04, p=0.04), PVTT (HR, 1.70; 95% CI, 1.13-2.56, p=0.01), hypoalbuminemia (≤3.5 g/dL) (HR 1.64; 95% CI 1.17-2.30, p&lt;0.01), and prior treatment experience (HR 1.61; 95% CI 1.00-2.57, p=005) were independently associated with poor 5-year OS by multivariate Cox regression analysis. Sarcopenia, PVTT, multifocal tumor, and prior treatment experience were independent predictors of PFS in multivariate analysis. Conclusions: TARE is an effective therapy for patients with advanced HCC. In patients undergoing TARE, Sarcopenia and PVTT are independent predictors of both OS and PFS.
Real-world representativeness of patient-reported outcome measures of patients with esophagogastric cancer.
Authors: Steven C. Kuijper, Joost Besseling, Thomas Klausch, Marije Slingerland, Charlène van der Zijden, Ewout Kouwenhoven, Laurens V. Beerepoot, Nadia Haj Mohammad, Bastiaan Klarenbeek, Rob Verhoeven, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2023)

319 Background: The use of patient reported outcome measures (PROMs) is a popular method to obtain real-world patient data in oncological research. However, PROMs rely on voluntary and active participation of patients and are therefore prone to selection bias. To investigate the suitability of PROMs as real-world data, we investigated the real-world representativeness of the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) registry with respect to the Dutch population of patients with esophagogastric cancer. Methods: We identified 2,575 patients in the POCOP registry and 13,702 in the nationwide population-based Netherlands Cancer Registry (NCR) from 2016-2021. We used Representativeness-indicators (R-indicators) to investigate the degree to which the POCOP registry and clinically relevant subgroups thereof, were a representative sample with respect to the population. R-indicators express the representativeness between 0 (not representative) and 1 (perfect representativeness). Calibration methods using inverse propensity weighting were used to correct potential differences between POCOP and the population estimates. Subsequently, median and 5-year overall survival were calculated and compared between patients in the POCOP registry and in the population, to investigate the representativeness in terms of survival. Results: Representativeness of the entire POCOP registry was 0.73 (95% CI: 0.71-0.74). The overall representativeness of palliative patients was higher than that of potentially curable patients (0.89 (0.87-0.90) and 0.70 (0.68-0.71), respectively). Representativeness of most clinical subgroups stratified to treatment was good; R-indicators ranged between 0.8 to 1.0. Median survival of the NCR, POCOP and calibrated POCOP was 19, 32, and 23 months, respectively. The 5-year overall survival of patients in the NCR, POCOP and calibrated POCOP was 26%, 36%, and 27%, respectively. Conclusions: The real-world representativeness of patients who participated in PROMs was good when we accounted for treatment. This shows that in the analysis of PROMs stratification to treatment groups can lead to generalizable results to the population. Using complete non-stratified PROMs, real-world representativeness was lower and calibration methods could be used to correct differences between patients in the PROMs and the population.
Gunagratinib, a highly selective irreversible FGFR inhibitor, in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR pathway alterations: A phase IIa dose-expansion study.
Authors: Ye Guo, Chunwang Yuan, Weimin Ding, Yi Gao, Xu Zhu, Jieer Ying, Meili Sun, Jingdong Zhang, Zhixiang Zhuang, Yangqing Huang, Lichun Deng, Ping Chen, Yuxian Bai, Zuoxing Niu, Wei Li, Xiaoyu Yin, Aibing Xu, Yufeng Cheng, Jin Li
Journal: Journal of Clinical Oncology (2023)

572 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]
Prevalence and genomic landscape of BRAF alterations across gastrointestinal cancers.
Authors: David Driscoll, Min Wang, Fadel S. Alyaqoub, Sameer S. Udhane, Szabolcs Szelinger, Aimee Jalkanen, David W. Hall, Jess R Hoag, Janine R. LoBello, Frederick L. Baehner, Snehal Govind Thakkar, Gargi D. Basu
Journal: Journal of Clinical Oncology (2023)

806 Background: BRAF V600E mutations can lead to activation of the MEK/ERK pathway. The combination of dabrafenib plus trametinib was recently FDA-approved for use in these BRAF V600E altered unresectable or metastatic cancers. BRAF non-V600 alterations also increase phosphorylation of MEK and ERK and are potential candidates for MEK/ERK inhibitors. Here we examine the frequency of BRAF mutations and their genomic background across GI cancers. Methods: The Oncomap ExTra genomic profiling assay utilizes tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations in tumors. The assay detects single-nucleotide substitutions, indels, copy number alterations, alternative transcripts, and gene fusions. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also assessed. The frequency of BRAF and other gene alterations were identified across all GI cancers. Reported BRAF alterations were limited to those linked to an FDA approved therapy, clinical trial eligibility, and those deemed significant from review of the literature. Results: A total of 1927 patients with GI cancers were assayed between April 2018 to July 2022. The BRAF gene was mutated in 85 (4.4%) patients, which included 53 (2.8%) that were V600E and 32 (1.5%) that were non-V600, representing 37.6% of BRAF mutations. Colorectal and small bowel cancers had the highest frequencies of BRAF mutations at 7.6% and 7.1% respectively, and the frequency was lower in other GI cancers (0-2.3%). In addition to BRAF V600E, other mutations occurred across the kinase domain, including D594 (0.6%), K601E (0.3%), G466 (0.3%) and G469 (0.2%). BRAF fusions were found in 1 CRC and 2 pancreatic cancer cases. BRAF mutational status (altered versus not) was significantly associated with mutations in several other genes. In addition, BRAF status was significantly associated with TMB-high and MSI-high. Conclusions: Analysis of whole-exome and whole transcriptome sequencing data found actionable BRAF mutations in 4.4% of GI cancer patients, 37.6% of whom had BRAF mutations not at V600. Several biomarkers were significantly associated with BRAF alterations. Assays that are limited to DNA sequencing, or to targeted gene panels, may not detect mutations and fusions that could aid in therapy selection and prognosis. [Table: see text]
Concordance in oncogenic alterations between primary and recurrent/metastatic cholangiocarcinoma pairs using targeted next-generation sequencing.
Authors: Sarah Margaret Helena McIntyre, William Preston, Henry S. Walch, Carlie S. Sigel, Jeremy Sharib, Wei Chen, Michael Lidsky, Ritika Kundra, Andrea Cercek, James J. Harding, Ghassan K. Abou-Alfa, Vinod P. Balachandran, Jeffrey A. Drebin, Kevin Soares, Alice Chia-chi Wei, T. Peter Kingham, Michael Ian D'Angelica, Christine A Iacobuzio-Donahue, Nikolaus Schultz, William R. Jarnagin
Journal: Journal of Clinical Oncology (2023)

604 Background: The genetic background of cholangiocarcinoma (CCA) commonly involves alterations in kinase signaling, tumor suppression, oxidative stress modulation, and proto-oncogenic coupling pathways. Novel agents targeting such pathways have shown promise in systemic treatment; however, studies examining differences in the mutational landscapes between primary and recurrent, metastatic, or progressive disease after systemic therapy are lacking. The present study aimed to determine if recurrent, metastatic, or progressive disease genetically parallels the primary or not. Methods: Patients with biopsy proven CCA (primary tumor and paired recurrent/metastatic or progressive disease) from two institutions (MSKCC and Duke) were identified. Targeted next-generation sequencing (Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)) capturing single nucleotide variants, copy number alterations, and structural variants was used to compare driver alteration concordance across the paired samples. Subgroup analyses were performed based on exposure to systemic therapy in patients with disease progression and tumor type (intrahepatic versus extrahepatic). Results: Sample pairs from 65 patients with intrahepatic (ICCA, n=54) and extrahepatic CCA (ECCA, n=11) were analyzed. Median time between samples was 19.6 months (range 2.7 - 122.9). Some de novo alterations were identified in recurrent/metastatic samples, but overall concordance (70%) was demonstrated between patient pairs for common oncogenic driver genes (Table). Subgroup analyses of summative ICCA and ECCA mutations revealed concordance of 65% and 88%, respectively. Concordance was also demonstrated between pairs exposed to systemic therapy between sample collections (n=50, 71%). Conclusions: In this dataset of CCA patients, a concordance rate of 70% was identified in the genomic alterations between primary and recurrent/metastatic pairs, and this did not appear to be altered by prior treatment with systemic chemotherapy. While limited by sample size, concordance in ICCA pairs was lower than that seen in ECCA. [Table: see text]
Effectiveness of biologic agents among Hispanics in the US with metastatic colorectal cancer.
Authors: Riya Jayesh Patel, Abdissa Negassa, Seda Tolu, Ana Acuna Villaorduna, Sanjay Goel
Journal: Journal of Clinical Oncology (2023)

16 Background: Randomized clinical trials have demonstrated the survival benefit provided by the addition of biologic drugs to chemotherapy (biochemotherapy) in patients with metastatic colorectal cancer (mCRC). However, Hispanic patients are underrepresented in trial populations with limited data on treatment efficacy in them. We aim to compare effectiveness of chemotherapy vs biochemotherapy among Hispanic population in the US with mCRC. Methods: This study includes two cohorts of patients: 1. age ≥ 65 years mCRC diagnosed from 2004 to 2011 who had received at least 1 dose of chemotherapy and had complete Medicare claims data using the Surveillance, Epidemiology, and End Result (SEER)–Medicare linked database, and 2. local Hispanic population from two hospitals in Bronx, New York, from 2006- 2020. Patient data were classified according to whether they received chemotherapy (oxaliplatin, irinotecan, and 5-fluorouracil or capecitabine) or biochemotherapy (bevacizumab, cetuximab, panitumumab, ramucirumab, or aflibercept, started within 3 months of chemotherapy). Overall survival (OS) was defined as the time from starting chemotherapy to death or last follow-up. A weighted Cox regression model was used to assess differences in survival. Results: A total of 188 patients with mCRC were identified. Fifty three (28.2%) received chemotherapy and 135 (71.8%) received biochemotherapy. Median ages were 69 and 68 years, respectively. There were no differences based on median income, marital status, primary site or sidedness, tumor differentiation grades or Charlson Comorbidity Score between both groups. Among patients who received only chemotherapy, 9% received second or greater lines of chemotherapy when compared to 51% in the biochemotherapy group (p &lt;0.001). The median overall survival was 6.6 (95% CI:5.7 - 15.0) months (mo) and 15.9 (12.0 -24.5) mo, respectively. Biochemotherapy conferred an OS benefit with average HR=0.62 (0.41-0.94; p=0.023). This was most evident in the first year (HR=0.53, 0.31-0.89; 0.016), less so in 2nd year (HR=0.65, 0.28 - 1.49; 0.307) and there was an apparent reversal effect beyond 2 years (HR=1.79, 0.41-7.77; 0.436). Conclusions: In this comparative effectiveness study of a cohort of Medicare recipients and the Bronx population, with mCRC, biochemotherapy was associated with an improvement in OS, especially in the 1 st year. Patients receiving biochemotherapy are more likely to receive further lines of chemotherapy upon disease progression.